George was born on 21 October 1449 in Dublin at a time when his father was beginning to challenge Henry VI for the crown. His godfather was James FitzGerald, 6th Earl of Desmond. He was the third of the four sons of Richard and Cecily who survived to adulthood. Following his father's death and the accession of his elder brother, Edward, to the throne, George was created Duke of Clarence in 1461 and invested as a Knight of the Garter.

Clarence had actively supported his elder brother's claim to the throne, but following his marriage, he began to play a dangerous game. When his father-in-law the Earl of Warwick became discontented and jealous, and deserted Edward to ally himself with Margaret of Anjou, consort of the deposed King Henry, Clarence joined him in France, taking his pregnant wife. She gave birth to their first child, Anne, on 16 April 1470, in a ship off Calais. The child died shortly afterward. Henry VI rewarded Clarence by making him next in line to the throne after Edward of Westminster, justifying the exclusion of Edward IV either by attainder for his treason against Henry or on the grounds of his alleged illegitimacy.

After a short time, Clarence realized that his loyalty to his father-in-law was misplaced: Warwick had his younger daughter, Anne, marry Edward of Westminster, King Henry VI's heir. Since it now seemed unlikely that Warwick would replace Edward IV with Clarence, Clarence changed sides.

Warwick's efforts to return Henry VI to the throne ultimately failed and Warwick was killed in battle. George was restored to royal favour by his brother King Edward. As his father-in-law was dead, George became jure uxoris Earl of Warwick, but did not inherit the entire Warwick estate as his younger brother, Richard, Duke of Gloucester, married the widowed younger sister of his wife, Anne Neville, for which George resented his brother. George was created 1st Earl of Warwick [England] on 25 March 1472.(Alison Weir, Britain's Royal Family: A Complete Genealogy (London, U.K.: The Bodley Head, 1999), page 136.)

Like the first lords of Richmond, North Yorkshire|, Peter of Savoy, Earl of Richmond and Ralph de Neville, 1st Earl of Westmorland before him, George was endowed with the lordship of Richmondshire but without the peerage.

The Neville sisters were heiresses to their mother's considerable estates, and their husbands vied with one another for pride of place, with Richard eventually winning out. Clarence, who had made the mistake of plotting against his brother Edward IV, was imprisoned in the Tower of London and put on trial for treason. (In Shakespeare's Richard III, he is framed for treason by Richard.) Following his conviction, he was "privately executed" at the Tower on 18 February 1478, and the tradition grew up that he was drowned in a butt of Malmsey wine. (http://www.thepeerage.com/p10164.htm#i101637 Sir George Plantagenet, 1st Duke of Clarence]. Person Page 10164. Thepeerage.com. Retrieved on 2012-07-09.) The tradition may have originated in a joke, based on his reputation as a heavy drinker. However, a butt was equal to three hogsheads — 477.3 litres (105 imperial gallons) easily enough to drown in. A body, believed to be that of Clarence, which was later exhumed, showed no indications of beheading, the normal method of execution for those of noble birth at that time. (Hicks (1992), pp. 184–6). Another possibility is that George's remains were sent to the abbey in a barrel of Malmsey, as Horatio Nelson's were sent home in a barrel of brandy. In Shakespeare's Richard III he is stabbed by one of the Murderers after he convinces the other not to stab him, and then drowned in a vat of Malmsey, though off-stage. In Richard III (1955 film), after he is clubbed over the head into unconsciousness by the murderers, the drowning is shown, but in the 1995 version his throat is slit while in the bath.

Clarence's wife Isabel died in 1476, two months after giving birth to a short-lived son named Richard (6 October 1476 – 1 January 1477), and they are buried together at Tewkesbury Abbey in Gloucestershire. Their surviving children, Margaret and Edward, were cared for by their aunt, Anne Neville, until she died in 1485, when Edward was 10 years old.